The Upstream Sequence of a New Growth/Differentiation Factor, Midkine (MK), Mediates Developmentally Regulated lac Z Gene Expression in Transgenic Mice.

Abstract

Midkine (MK) is the product of a retinoic acid responsive gene, and is a heparin binding protein involved in the regulation of growth and differentiation. The 1.9 kb upstream region of MK gene was fused with the bacterial β-galactosidase gene (lac Z) and injected into fertilized mouse eggs. The resulting transgenic mice were used to evaluate the in vivo transcriptional regulation through of the upstream region. Comparison of the β-galactosidase expression and endogenous MK expression indicated that the temporal regulation of the transgene was similar to that of MK gene expression during mouse development. The transgene was neither expressed in the preimplantation period nor in 6.5-day embryos. Transgene expression was high and widely distributed on the 8.5th day, became restricted on the 10.5th and 12.5th days, and thereafter almost confined to the kidney. Thus, the 1.9 kb upstream region accounts for overall temporal regulation of MK gene expression, while there are some differences between the spatial regulation of the transgene expression and that of the endogenous MK gene expression. The transgene was expressed in a few limited regions of the brain of 17 day old embryos, and those sites consisted largely of matrix cells with columnar arrangements. These results suggests a role of MK in the brain development, and MK activity may be involved in retinoic acid induced malformations of the central nervous system.